This application addresses the broad Challenge Area 03: Biomarker Discrimination and Validation, and the specific challenge topic: 03-MG-101, Biomarkers of mental disorders. Schizophrenia, a devastating psychiatric disorder, is chiefly characterized by positive symptoms, such as delusions and hallucinations, and negative symptoms, such as anhedonia (lack of pleasure), avolition (lack of willed-action), and a flattening of affect. While antipsychotic medications reduce positive symptoms, they provided little relief from negative symptoms. Thus patients with severe negative symptoms are likely to suffer continued functional decline, and have a very limited life. We believe that the lack of progress on treating negative symptoms may be due, in part, to the fact that they are typically measured by subjective means (e.g., a clinician's rating, a patient's self-report), and taken at face value. Our goal is to use as markers of negative symptoms the patients'neural responses to various rewards and losses while having their brains scanned by functional Magnetic Resonance Imaging (fMRI). Further, we will determine the consequences of these negative symptoms for basic learning processes. In our first experiment, we will test patients with schizophrenia as well as normal subjects (who are matched to the patients on factors like age and gender) on the same learning task. On each trial of the task, a subject has to decide which of two objects is more likely to lead to a reward (e.g., money), where the probability that each object leads to reward keeps changing slowly. The precise sequence of events on a trial is as follows: (1) the subject first makes a Choice between the objects, (2) next gets Feedback whether his/her choice is correct or wrong, and (3) then gets the actual Outcome--a monetary reward if the choice was Correct, and nothing if the choice was Wrong. Over trials, subjects gradually learn to choose the object that is more likely to lead to reward. To see the connection between this task and negative symptoms, consider the time interval between the Feedback and the Outcome phases. If the feedback is positive the subject should be anticipating reward during this interval, and the neural responses should reflect "anticipatory hedonia". Now consider the time interval between the actual Outcome and the start of the next trial. If money is the Outcome the subject should have a hedonic reaction, and the neural responses should reflect "reactive hedonia". Based on previous research, we know which regions of the brain are responsive to hedonic reactions, one of which is the ventral striatum, a subcortical area. By determining each subject's fMRI activity in these regions during the two time intervals just described, we can determine whether patients with schizophrenia show reduced anticipatory-hedonia, reduced reactive-hedonia, or both. Some behavioral experiments suggest that the main deficit for schizophrenics will be in anticipatory-hedonia, and accordingly we hypothesize that there will be more fMRI activity in the regions of interest in normal subjects than patients when subjects are anticipating a reward, but not necessarily when they are reacting to a reward. The degree of fMRI activity when anticipating a reward may provide a biological marker for the negative symptom of anhedonia;to assess this possibility, we will correlate our fMRI measure with standard clinical measures of anhedonia. We will also determine whether patients with schizophrenia and matched controls differ in their learning processes. When normal controls have their brains imaged while performing this learning task, the ventral striatum is among the main regions activated. Since the same brain region is involved in both learning and hedonia, and since patients show less activity in this region when anticipating a reward, patients may also be impaired in learning. It's not just that both mental activities depend on the same brain region;it's also that learning in this kind of task is known to depend on making predictions about whether reward will occur on that trial, and the prediction process itself seems to be fueled by anticipatory hedonia. Our second experiment is like the first one, except that instead of gaining rewards on some trials now subjects will lose money when their choice is Wrong (their losses will be taken from money given to them at the outset of the experiment). Again, each trial includes three phases: Choice, Feedback, and Outcome, with the latter being either a loss (following the feedback "Wrong"), or nothing (following the feedback "Correct"), and now the subject's goal is to learn to make the choice that will lead to less loss. If the feedback indicates a loss is coming, fMRI activity during the interval between Feedback and Outcome reflects anticipatory-displeasure (or avoidance), while the interval between the Outcome and the end of trial reflects reactive-displeasure. Should we find that, compared to matched controls, patients with schizophrenia again show less fMRI activity during the anticipatory-interval but not during the reactive-interval, we will have biological markers for another negative symptom, affective flattening, or reduced reactivity to emotional states be they positive or negative. PUBLIC HEALTH RELEVANCE: While standard antipsychotic medications reduce the positive symptoms of schizophrenia (e.g., delusions), they provide little benefit for the devastating negative symptoms of this disease (e.g., anhedonia, flattening of affect). The lack of progress in treating negative symptoms may be due to the fact that they are often measured by subjective means (a clinician'rating, a patient's self-report). Our goal is to use brain imaging to provide objective and biological markers of the various negative symptoms.